Correlation between clastogenicity and promotion activity in liver carcinogenesis by N-hydroxy-2-acetylaminofluorene, N-hydroxy-4'-fluoro-4-acetylaminobiphenyl and N-hydroxy-4-acetylaminobiphenyl.
N-Hydroxy-2-acetylaminofluorene (N-OH-AAF), N-hydroxy-4'-fluoro-4-acetylaminobiphenyl (N-OH-FAABP) and N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP) were compared for their initiation and promotion activity in the rat liver using a modified Solt-Farber system. N-OH-AAF, N-OH-FAABP and N-OH-AABP showed comparable initiation capacity when administered to male Wistar rats at a dose of 30, 120 and 120 mumol/kg respectively, 24 h after a two-thirds partial hepatectomy (PH). In contrast, only N-OH-AAF was very effective as promoter when administered to rats previously initiated with diethylnitrosamine. This was evidenced by a high number of large gamma-glutamyltranspeptidase-positive (GGT+) foci occupying a high percentage (22%) of liver volume. N-OH-FAABP was a much weaker promoter, resulting in smaller foci and lower percentage (4%) of GGT+ liver volume. The incomplete carcinogen N-OH-AABP was totally ineffective as promoter in our model. A similar difference was seen in the clastogenicity of these carcinogens in rat liver in vivo as measured by the formation of micronuclei: N-OH-AAF was far more clastogenic than N-OH-FAABP, which in turn was more clastogenic than N-OH-AABP. We have recently shown that N-acetylated deoxyguanosine adducts are responsible for clastogenicity of N-OH-AAF and may be important for promotion. DNA adduct analysis after injection of 120 mumol/kg of tritium-labeled N-OH-FAABP or N-OH-AABP, 24 h after PH, showed that N-acetylated adducts to C8 of deoxyguanosine are also formed from these structurally related liver carcinogens. However, the formation of these adducts from N-OH-FAABP and N-OH-AABP was approximately 8 and approximately 5% of the formation of dG-C8-AAF after injection of 25 mumol/kg N-OH-AAF. These data show that for the structurally related liver carcinogens N-OH-AAF, N-OH-FAABP and N-OH-AABP, clastogenicity does not predict initiating efficacy but correlates with promotion activity. Possibly, N-acetylated adducts to C8 of deoxyguanosine are involved in both clastogenicity and promotion.
van de Poll
M L
ML
Department of Toxicology, University of Leiden, The Netherlands.
van der Hulst
D A
DA
Tates
A D
AD
Meerman
J H
JH
D015073:2-Acetylaminofluorene; D000611:Aminobiphenyl Compounds / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002273:Carcinogens; D004247:DNA / Q000378:metabolism; D006881:Hydroxyacetylaminofluorene / Q000378:metabolism / Q000633:toxicity*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D009153:Mutagens; D051381:Rats; D011919:Rats, Inbred Strains
D000611:Aminobiphenyl Compounds; D002273:Carcinogens; D009153:Mutagens; C001365:N-hydroxy-4-acetylaminobiphenyl; D006881:Hydroxyacetylaminofluorene; C017373:N-hydroxy-4-acetylamino-4'-fluorobiphenyl; D004247:DNA; D015073:2-Acetylaminofluorene